CD30-Positive Extracellular Vesicles Enable the Targeting of CD30-Negative DLBCL Cells by the CD30 Antibody-Drug Conjugate Brentuximab Vedotin

Abstract

CD30, a member of the TNF receptor superfamily, is selectively expressed on a subset of activated lymphocytes and on malignant cells of certain lymphomas, such as classical Hodgkin Lymphoma (cHL), where it activates critical bystander cells in the tumor microenvironment. Therefore, it is not surprising that the CD30 antibody-drug conjugate Brentuximab Vedotin (BV) represents a powerful, FDA-approved treatment option for CD30+ hematological malignancies. However, BV also exerts a strong anti-cancer efficacy in many cases of diffuse large B cell lymphoma (DLBCL) with poor CD30 expression, even when lacking detectable CD30+ tumor cells. The mechanism remains enigmatic. Because CD30 is released on extracellular vesicles (EVs) from both, malignant and activated lymphocytes, we studied whether EV-associated CD30 might end up in CD30– tumor cells to provide binding sites for BV. Notably, CD30+ EVs bind to various DLBCL cell lines as well as to the FITC-labeled variant of the antibody-drug conjugate BV, thus potentially conferring the BV binding also to CD30– cells. Confocal microscopy and imaging cytometry studies revealed that BV binding and uptake depend on CD30+ EVs. Since BV is only toxic toward CD30– DLBCL cells when CD30+ EVs support its uptake, we conclude that EVs not only communicate within the tumor microenvironment but also influence cancer treatment. Ultimately, the CD30-based BV not only targets CD30+ tumor cell but also CD30– DLBCL cells in the presence of CD30+ EVs. Our study thus provides a feasible explanation for the clinical impact of BV in CD30– DLBCL and warrants confirming studies in animal models.

Anti-CD30 antibody–drug conjugate therapy in lymphoma: current knowledge, remaining controversies, and future perspectives

“…CD30 is variably expressed in DLBCL, at a frequency of up to 60% depending on cut-off value [ 4 , 108 ], but unexpectedly, some studies have suggested that the response to brentuximab vedotin treatment does not correlate with CD30 expression [ 109 ]. This has led to a hypothesis that CD30-positive extracellular vesicles can transport brentuximab vedotin to CD30-negative tumor cells (a theory that is borne out by preclinical data) [ 109 ].…”

Evolving Landscape of Antibody Drug Conjugates in Lymphoma

“…Brentuximab vedotin can also affect CD30-antigen-negative cancer cells through bystander effects, although the extent of this is unknown. 7,25 Currently, BV is approved for patients with relapsed or refractory (R/R) Hodgkin lymphoma and CD30-positive anaplastic large cell lymphoma (Table 2). The drug is also approved for high-risk Hodgkin lymphoma treated with autologous stem cells and CD30-expressing myelofibrosis and cutaneous T-cell lymphoma (TCL).…”

“…However, other factors in the tumor microenvironment may modulate response. 7,25 Another phase I trial evaluated the combination of BV and lenalidomide in the R/R DLBCL. 43 Of the enrolled 37 patients, 22 of the DLBCLs were negative for CD30.…”

“…Free MMAE targets tubulin, inhibiting its polymerization, leading to cell cycle arrest and apoptosis. Brentuximab vedotin can also affect CD30-antigen–negative cancer cells through bystander effects, although the extent of this is unknown 7,25 . Currently, BV is approved for patients with relapsed or refractory (R/R) Hodgkin lymphoma and CD30-positive anaplastic large cell lymphoma (Table 2).…”

Bone Marrow Lymphoid Niche Adaptation to Mature B Cell Neoplasms

“…However, as CD30 pos bystander cells are enriched in the tumor tissue in many cases of DLBCL, CD30 might be released within TME-derived EVs. Thus a model was proposed in which even in the absence of CD30 on the tumor cells, EVs can transport the targeting protein from cells of the TME to tumor cells ( 116 ). This model would explain the clinical efficacy of Brentuximab vedotin also in cases of lack of the targeting antigen on tumor cells.…”